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1.
Int J Mol Sci ; 25(7)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38612711

RESUMO

Breast cancer is the most common malignancy and its incidence is increasing. It is currently mainly treated by clinical chemotherapy, but chemoresistance remains poorly understood. Prefolded proteins 4 (PFDN4) are molecular chaperone complexes that bind to newly synthesized polypeptides and allow them to fold correctly to stabilize protein formation. This study aimed to investigate the role of PFDN4 in chemotherapy resistance in breast cancer. Our study found that PFDN4 was highly expressed in breast cancer compared to normal tissues and was statistically significantly associated with stage, nodal status, subclasses (luminal, HER2 positive and triple negative), triple-negative subtype and disease-specific survival by TCGA database analysis. CRISPR knockout of PFDN4 inhibited the growth of 89% of breast cancer cell lines, and the triple-negative cell line exhibited a stronger inhibitory effect than the non-triple-negative cell line. High PFDN4 expression was associated with poor overall survival in chemotherapy and resistance to doxorubicin and paclitaxel through the CREBP1/AURKA pathway in the triple-negative MDAMB231 cell line. This study provides insightful evidence for the value of PFDN4 in poor prognosis and chemotherapy resistance in breast cancer patients.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Aurora Quinase A , Prognóstico , Mama , Células MCF-7
2.
Sci Rep ; 13(1): 17872, 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37857745

RESUMO

Based on some studies, there are many important parts of tool machines, all of which have some essential smaller-the-better-type quality characteristics. The six sigma quality index of the smaller-the-better type offers accurate measurement of the process yield and the six sigma quality level. In this paper, we first proposed a six sigma product index by integrating all evaluation indicators for products that contain several quality characteristics of the smaller-the-better type. Next, we derived the confidence interval of this six sigma product index and developed an evaluation model for product quality. When a product passes the evaluation of this model, not only can it be guaranteed that the product reaches the required quality level, but also a high rate of product yield can be ensured. In addition, we also created a product improvement testing model, which can avoid missing opportunities for improvement in the process to ensure improvement effects. This complete evaluation and improvement model is applicable to the entire machine tool industry chain. It can not only increase the product value of the machine tool industry chain but also decrease environmental pollution caused by rework or scrap, which is beneficial to companies to enhance their image of fulfilling social responsibilities. Apart from the above advantages, the model formed in this paper is based on confidence intervals, thereby reducing the chance of misjudgment resulting from sampling error.

3.
Biomed Pharmacother ; 161: 114500, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36958195

RESUMO

Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis is related to ARID1A mutation mediating the expression of HDAC6, but the detailed pathogenic mechanism is still unclear. First, we collected endometriosis-associated ovarian carcinoma (EAOC) clinical samples and examined the expression of HDAC6. Our results found that the high HDAC6 expression group was positively correlated with EAOC histology (P = 0.015), stage (P < 0.000), and tumor size (P < 0.000) and inversely correlated with survival (P < 0.000). We also found that ARID1A6488delG/HDAC6 induced M2 polarization of macrophages through IL-10. In addition, the HDAC inhibitor (HDACi) vorinostat inhibited cell growth and blocked the effect of HDAC6. Tomographic microscopy was used to monitor the live cell morphology of these treated cells, and we found that vorinostat treatment resulted in substantial cell apoptosis by 3 h 42 min. Next, we established a transgenic mouse model of EAOC and found that vorinostat significantly reduced the size of ovarian tumors by inhibiting M2 macrophage polarization in mice. Together, these data demonstrate that the signaling pathway of E4F1/ARID1A6488delG/HDAC6/GATA3 mediates macrophage polarization and provides a novel immune cell-associated therapeutic strategy targeting IL-10 in EAOC.


Assuntos
Carcinoma , Endometriose , Neoplasias Ovarianas , Humanos , Feminino , Animais , Camundongos , Vorinostat/farmacologia , Endometriose/patologia , Interleucina-10 , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Transdução de Sinais , Macrófagos/patologia , Proteínas de Ligação a DNA , Fatores de Transcrição , Desacetilase 6 de Histona , Proteínas Repressoras
4.
Cells ; 11(12)2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35741053

RESUMO

The new coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been reported and spread globally. There is an urgent need to take urgent measures to treat and prevent further infection of this virus. Here, we use virtual drug screening to establish pharmacophore groups and analyze the ACE2 binding site of the spike protein with the ZINC drug database and DrugBank database by molecular docking and molecular dynamics simulations. Screening results showed that Venetoclax, a treatment drug for chronic lymphocytic leukemia, has a potential ability to bind to the spike protein of SARS-CoV-2. In addition, our in vitro study found that Venetoclax degraded the expression of the spike protein of SARS-CoV-2 through amino acids Q493 and S494 and blocked the interaction with the ACE2 receptor. Our results suggest that Venetoclax is a candidate for clinical prevention and treatment and deserves further research.


Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Aminoácidos/metabolismo , Enzima de Conversão de Angiotensina 2 , Compostos Bicíclicos Heterocíclicos com Pontes , Humanos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/química , Sulfonamidas
5.
Curr Issues Mol Biol ; 44(5): 2107-2121, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35678671

RESUMO

Taraxacum officinale (dandelion) is often used in traditional Chinese medicine for the treatment of cancer; however, the downstream regulatory genes and signaling pathways mediating its effects on breast cancer remain unclear. The present study aimed to explore the effects of luteolin, the main biologically active compound of T. officinale, on gene expression profiles in MDA-MB-231 and MCF-7 breast cancer cells. The results revealed that luteolin effectively inhibited the proliferation and motility of the MDA-MB-231 and MCF-7 cells. The mRNA expression profiles were determined using gene expression array analysis and analyzed using a bioinformatics approach. A total of 41 differentially expressed genes (DEGs) were found in the luteolin-treated MDA-MB-231 and MCF-7 cells. A Gene Ontology analysis revealed that the DEGs, including AP2B1, APP, GPNMB and DLST, mainly functioned as oncogenes. The human protein atlas database also found that AP2B1, APP, GPNMB and DLST were highly expressed in breast cancer and that AP2B1 (cut-off value, 75%) was significantly associated with survival rate (p = 0.044). In addition, a Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were involved in T-cell leukemia virus 1 infection and differentiation. On the whole, the findings of the present study provide a scientific basis that may be used to evaluate the potential benefits of luteolin in human breast cancer. Further studies are required, however, to fully elucidate the role of the related molecular pathways.

6.
Curr Issues Mol Biol ; 44(5): 2243-2256, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35678681

RESUMO

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world, and the incidence and death rate of OSCC in men is twice that of women. CD47 is a ubiquitous cell surface transmembrane protein, also known as integrin-related protein (IAP). Previous studies have pointed out that CD47 can inhibit the growth of OSCC, but the detailed mechanism is not clear. This study aimed to explore the effect of CD47 gene expression profiles in OSCC. The OSCC cell lines, OECM-1 and OC-2, overexpressed CD47, and the expression profiles of mRNAs were analyzed through next-generation sequencing (NGS) with a bioinformatic approach. A total of 14 differentially expressed genes (DEGs) were listed. In addition, ingenuity pathway analysis (IPA) was used to analyze the molecular function (MF), biological process (BP), and cellular component (CC) network signaling. The human protein atlas (HPA) database was used to analyze gene expression and the survivability of human cancer. The results found that HSPA5, HYOU1, and PDIA4 were involved in the IPA network and when highly expressed, mediated the survivability of cancer. In addition, HSPA5 was positively and significantly correlated with CD47 expression (p < 0.0001) and induced by CD47-overexpression in the OECM-1 and OC-2 OSCC cancer cell lines. These findings provide important insights into possible new diagnostic strategies, including unfolded protein for OSCC-targeting CD47.

7.
Sci Rep ; 12(1): 10513, 2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35732647

RESUMO

Oral squamous cell carcinoma (OSCC) is a common malignant tumor worldwide that is characterized by abnormal lesions or malignant hyperplasia of soft and hard tissues in the oral cavity. Previous research has found that HDAC6 may be a potential therapeutic target for cancer patients and has the ability to regulate immune cells. However, the mechanism of HDAC6 in OSCC pathogenesis is unclear. We collected clinical samples and analyzed the level of HDAC6 in OSCC patients. The results showed that in the high HDAC6 expression group, HDAC6 expression was positively correlated with the grade of OSCC (R = 0.182, P = 0.036) and that this group had a 3.248-fold increase in the mortality risk compared with the low HDAC6 expression group (P = 0.003). Survival analysis also identified a correlation between the expression of HDAC6 and overall survival in OSCC patients, and it was found that the expression of HDAC6 was inversely correlated with survival (P ≤ 0.001). In addition, we found that HDAC6 induced IL-13 expression through AP-1, resulting in M2 polarization of macrophages. Together, these results demonstrate that the level of HDAC6 may be a useful prognostic biomarker and offer a novel immune cell-related therapeutic strategy of targeting IL-13 in OSCC.


Assuntos
Desacetilase 6 de Histona , Macrófagos , Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Biomarcadores/metabolismo , Desacetilase 6 de Histona/genética , Desacetilase 6 de Histona/metabolismo , Humanos , Interleucina-13/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fator de Transcrição AP-1/metabolismo
8.
Sci Rep ; 12(1): 2858, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190574

RESUMO

The association between phthalate exposure and breast cancer remains controversial. We performed a prospective patient cohort design to explore the interaction between creatinine-corrected urinary phthalate metabolites and hormone receptors as well as body mass index (BMI) on recurrent breast cancer. In this follow-up study, 636 female breast cancer patients and 45 new recurrent cases diagnosed for a total of 1576.68 person-years of follow-up were recruited. Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively associated with breast cancer recurrence, with adjusted hazard ratio (aHR) 3rd vs. 1st quartile of 0.15 (95% CI 0.04-0.51). The MEOHP presented as a non-monotonic dose-response (NMDR) curve, being U-shaped. In the stratification of hormone receptors, MEOHP still exhibited a U-shaped dose-response curve. The third quartile of MEOHP showed significant lowest recurrent risk in the status of ER-positive (aHR 0.18, 95% CI 0.05-0.66), PR-negative (aHR 0.14, 95% CI 0.03-0.63), and HER2-negative (aHR 0.24, 95% CI 0.08-0.76). Whether in BMI < 25 or in BMI ≥ 25, the third quartile of MEOHP was negatively associated with recurrent breast cancer, and there was a negative interaction on an additive scale between MEOHP and BMI (pinteraction = 0.042). The association between MEOHP and recurrent breast cancer was modified by hormone receptors and BMI.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/etiologia , Exposição Ambiental/efeitos adversos , Resultados Negativos , Recidiva Local de Neoplasia/etiologia , Ácidos Ftálicos/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Biomed Pharmacother ; 145: 112400, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34801851

RESUMO

Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and found that Σ4MEHP (the sum of MEHP, MEHHP, MECPP and MEOHP concentrations) in urine was significantly higher (P = 0.018) in the recurrent breast cancer group compared with non-recurrent patients. Σ4MEHP-High was positively and significantly correlated with tumor stage (P = 0.005), lymph node status (P = 0.001), estrogen receptor status (P = 0.010), Her2/Neu status (P = 0.004), recurrence (P = 0.000) and tumor size (P = 0.002), as well as an independent prognostic marker (OR = 1.868; 95% CI = 1.424-2.451; P < 0.000) associated with poor survival rates based on a positive Her2/Neu status (P = 0.035). In addition, we found that DEHP inhibited paclitaxel and doxorubicin effects in breast cancer cell lines MCF-7 and MDA-MB-231 and in zebrafish and mouse tumor initiation models. DEHP induced trefoil factor 3 (TFF3) expression through the vinculin/aryl hydrocarbon receptor (AhR)/ERK signaling pathway and induced CYP2D6, CYP2C8 and CYP3A4 expression through the AhR genomic pathway to increase the epithelial-mesenchymal transition (EMT) and doxorubicin metabolism, respectably. DEHP mediated AhR-related alterations in estrogen receptor expression through the ubiquitination system, which decreased tamoxifen effects in AhR knockout mice. These findings suggest a novel therapeutic avenue by targeting AhR in drug-resistant and recurrent breast cancer.


Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Dietilexilftalato/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Adulto , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Knockout , Recidiva Local de Neoplasia , Paclitaxel/farmacologia , Receptores de Hidrocarboneto Arílico/genética , Taxa de Sobrevida , Tamoxifeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
10.
Molecules ; 26(21)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34770867

RESUMO

Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence. Recent studies have suggested that breast CSCs play essential roles in chemoresistance. Therefore, new agents that selectively target such cells are urgently required. Reactive oxygen species (ROS)-producing enzymes are the reason for an elevated tumor oxidant status. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes. By triggering a cytoprotective response, Nrf2 maintains cellular redox status. Cripto-1 participates in the self-renewal of CSCs. Herein, luteolin, a flavonoid found in Taraxacum officinale extract, was determined to inhibit the expressions of stemness-related transcriptional factors, the ATP-binding cassette transporter G2 (ABCG2), CD44, aldehyde dehydrogenase 1 activity as well as the sphere formation properties of breast CSCs. Furthermore, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features. The combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells. These findings suggest that luteolin treatment significantly attenuated the hallmarks of breast cancer stemness by downregulating Nrf2-mediated expressions. Luteolin constitutes a potential agent for use in cancer stemness-targeted breast cancer treatments.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Luteolina/química , Fator 2 Relacionado a NF-E2/metabolismo , Células Tumorais Cultivadas
11.
J Clin Endocrinol Metab ; 106(5): 1516-1529, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33507273

RESUMO

CONTEXT: Small extracellular vesicles (sEVs) have emerged as modulators of the disease microenvironment, thereby supporting disease progression. However, the potential role of EVs and their content to the pathophysiology of endometriosis remain unclear. OBJECTIVE: This work aimed to investigate whether the EVs from eutopic (Eu) and ectopic (Ec) endometrial stromal cells (ESCs) differ with respect to protein composition and role in endometriosis. METHODS: Human Eu and Ec endometrium-derived ESCs were isolated from samples of the same patients (n = 3). sEVs were isolated from ESCs via ultracentrifugation; these sEVs were characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis and analyzed using mass spectrometry. The potential role of EcESCs-derived sEVs (EcESCs-sEVs) in endometriosis was explored by assaying their effects on cell viability/proliferation, migration, and angiogenesis. RESULTS: In total, 105 ESCs-sEV-associated proteins were identified from EcESCs-sEVs and EuESCs-sEVs by mass spectrometry analysis. The protein content differed between EcESCs-sEVs and EuESCs-sEVs, with annexin A2 (ANXA2) being the most prominent difference-present in EcESCs-sEVs but not EuESCs-sEVs. We also found that sEVs-ANXA2 regulates the motility, proliferation, and angiogenesis of ESCs via the extracellularly regulated kinase (ERK)/STAT3 pathway. Notably, treatment of ESCs with sEVs-ANXA2 resulted in increased proliferation and motility, suggesting that sEVs-ANXA2 may be involved in regulating endometriosis. Our data suggest that EcESCs-sEVs-ANXA2 regulates the motility and the angiogenic potential of ESCs, implying a role for sEVs-ANXA2 in the pathogenesis of endometriosis. CONCLUSION: The study of sEVs-ANXA2 from Ec endometriotic cells uncovers a new mechanism of endometriosis progression and will inform the development of novel therapeutic strategies.


Assuntos
Endométrio/metabolismo , Vesículas Extracelulares/metabolismo , Células Estromais/metabolismo , Anexina A2/metabolismo , Anexina A2/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Endometriose/metabolismo , Endometriose/patologia , Endométrio/irrigação sanguínea , Endométrio/citologia , Vesículas Extracelulares/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Doenças Peritoneais/metabolismo , Doenças Peritoneais/patologia , Proteômica , Células Estromais/citologia
12.
Sci Rep ; 10(1): 17447, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060649

RESUMO

Mutant RAS genes play an important role in regulating tumors through lysine residue 104 to impair GEF-induced nucleotide exchange, but the regulatory role of KRAS K104 modification on the KRASG12D mutant remains unclear. Therefore, we simulated the acetylation site on the KRASG12D three-dimensional protein structure, including KRASG12D, KRASG12D/K104A and KRASG12D/K104Q, and determined their trajectories and binding free energy with GEF. KRASG12D/K104Q induced structural changes in the α2- and α3-helices, promoted KRAS instability and hampered GEF binding (ΔΔG = 6.14 kJ/mol). We found decreased binding to the Raf1 RBD by KRASG12D/K104Q and reduced cell growth, invasion and migration. Based on whole-genome cDNA microarray analysis, KRASG12D/K104Q decreased expression of NPIPA2, DUSP1 and IL6 in lung and ovarian cancer cells. This study reports computational and experimental analyses of Lys104 of KRASG12D and GEF, and the findings provide a target for exploration for future treatment.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/metabolismo , Sítios de Ligação , Movimento Celular , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Simulação de Dinâmica Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Oligonucleotídeos/genética , Neoplasias Ovarianas/metabolismo , Domínios Proteicos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Termodinâmica , Cicatrização
13.
Biomed Pharmacother ; 132: 110869, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33113427

RESUMO

Helicobacter pylori infection is an important pathogenic risk factor for gastric cancer, but it is still unclear what tumor markers for gastric cancer induced by H. pylori can be consistently detected. Using an miRNA microarray, we found that miR-18a-3p (6.02-fold) and miR-4286 (5.73-fold) were significantly increased in H. pylori- associated gastric cancer. In a cohort of gastric cancer patients (N = 104), serum expression of miR-18a-3p and miR-4286 was positively and significantly correlated with H. pylori; furthermore, miR-18a-3p was positively correlated with invasion (P = 0.029), and miR-4286 was positively correlated with tumor stage (P = 0.033), tumor size (P = 0.041), and lymph node metastasis (P = 0.009). Overexpression of miR-18a-3p and miR-4286 also increased cancer cell proliferation and motility and both inhibited expression of BZRAP1, resulting in tumor progression in vitro. In addition, lipopolysaccharide co-mediated the expression of miR-18a-3p and miR-4286 by activating the NF-κB transcription factor, but TAK-242 (TLR4 inhibitor) blocked this effect. These results demonstrate that serum miR-18a-3p and miR-4286 levels in H. pylori-associated gastric cancer may be useful prognostic biomarkers and suggest a novel signaling pathway of targeting BZRAP1 in gastric cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transformação Celular Neoplásica/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/complicações , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Receptor 4 Toll-Like/metabolismo
14.
Oncol Lett ; 20(1): 33-42, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32565931

RESUMO

It has been identified that bisphenol A (BPA) exposure causes developmental toxicity in breast cells. However, the exact molecular mechanisms underlying the association between exposure to BPA and breast cancer remain unclear. The aim of the present study was to investigate the BPA-regulated signaling pathways associated with the aggressiveness and the development of breast cancer. Microarray technology and functional gene set analyses were used to evaluate BPA and breast cancer-associated biomarkers and pathways in a discovery-driven manner. Using individual dataset analyses, it was indicated that two BPA-associated gene sets, the visceral obesity pathway, involved in visceral fat deposits and the metabolic syndrome, and the cell cycle pathway, involved in cyclins and cell cycle regulation, were significantly associated with a high grade of aggressiveness and the development of estrogen receptor (ER)-positive breast cancer (between P<0.05 and 0.0001). The pooled analysis indicated that the most significant pathway was G1/S checkpoint regulation, and the cyclin and cell cycle regulation pathway for BPA-associated ER-positive cancer. Cancer cell signaling pathways were associated with healthy breast cells developing into breast cancer. The visceral obesity and the cell cycle pathways were indicated to link BPA exposure to breast cancer. The results of the present study demonstrate a significant association between breast cancer and BPA-regulated gene pathways.

15.
Biomed Pharmacother ; 119: 109105, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493748

RESUMO

Endometriosis is considered a high risk factor for the development of ovarian carcinoma, including clear cell and endometrioid malignancies. The mechanism by which endometriosis-associated ovarian cancer (EAOC) avoids anti-tumor immune surveillance by macrophages remains unclear, but CD47 is a very important immune checkpoint for macrophage phagocytosis. Therefore, we collected 36 clinical ovarian samples and detected the protein profile of CD47 by immunohistochemistry and analyzed the correlation with clinical pathological features using statistical software. We found that CD47 expression was relatively higher in patients with EAOC compared with the normal group. High CD47 expression was positively and significantly correlated with histology (P = 0.007) and tumor grade (P = 0.002). We also found that CD47 overexpression promotes cancer cell growth and motility in the TOV-112D and TOV-21G cell lines. Silencing CD47 and anti-CD47 mAb inhibit cancer cell growth and motility in cancer cell lines. Together, these results demonstrate that CD47 in EAOC may be a useful surface marker and offer a novel therapeutic option by targeting CD47 in ovarian cancer.


Assuntos
Antígeno CD47/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Movimento Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica
16.
Mol Med Rep ; 19(3): 2341-2349, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664162

RESUMO

Cluster of differentiation (CD)44+/CD24- breast cancer cells have stem cell­like characteristics and are potent initiators of tumorigenesis. Mammosphere cells can partially initiate breast tumorigenesis by inducing estradiol (E2)­dependent breast cancer cells. However, the mechanisms by which E2 mediates cancer formation in MCF­7 mammosphere (MS) cells have remained elusive. In the present study, MS cells were isolated by sphere culture. It was possible to maintain these MS cells in culture for long periods of time, while retaining the CD44+/CD24- stem cell marker status. The CD44+/CD24- status was confirmed by flow cytometry. Furthermore, the stem­cell markers Musashi­1, cytokeratin (CK)7 and CK19 were identified by immunofluorescence microscopy. It was revealed that treatment of MS cells with E2 increased the expression of CD44, whereas decreased the expression of CD24 on MS cells. In addition, treatment with E2 increased colony formation by MS cells. E2 also induced cyclooxygenase­2 (COX­2) expression in MS cells, which promoted their proliferation through the estrogen receptor/human epidermal growth factor receptor 2 (HER2)/mitogen­activated protein kinase/phosphoinositide­3 kinase signaling pathway. The results suggested a tumorigenic mechanism by which E2 promotes tumor cell proliferation via HER2/COX­2 signaling. The present study provided evidence for the molecular impact of E2 on breast tumorigenesis, and suggested possible strategies for preventing and treating human breast cancer.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Ciclo-Oxigenase 2/genética , Receptor ErbB-2/genética , Antígenos CD/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CD24/genética , Proliferação de Células/efeitos dos fármacos , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Receptores de Hialuronatos/genética , Células MCF-7 , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
17.
Oncol Rep ; 40(6): 3734-3742, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542723

RESUMO

Ovarian cancer is the one of the most lethal gynecological cancer types. MicroRNAs (miRs) are noncoding RNAs that modulate the translation of their target mRNAs via binding to a complementary sequence in the target 3' untranslated region, and the dysregulation of certain miRs has been demonstrated to contribute to cancer progression. In this regard, the current study extended our previous work and used next­generation sequencing data to search for upstream regulators of genetic alterations that are common in ovarian cancer, as well as the miRs that are involved in controlling the expression of these regulators. An miR prediction program was used to identify miR­381 as an upstream regulator of phosphatidylinositol 3­kinase catalytic subunit α (PIK3CA) in the context of ovarian cancer. Levels of miR­381 were decreased in clear cell and endometrioid carcinoma ovarian cancer. Experimentally induced upregulation of miR­381 led to a decrease in the level of PIK3CA in ovarian cancer cells. Furthermore, experimentally induced upregulation of miR­381 inhibited the proliferation of ovarian cancer cells in vitro and their ability to form colonies and migrate. The observed decrease in miR­381 in ovarian cancer could be reversed upon overexpression of the gene encoding the tumor suppressor homeobox D10. The current results highlight the role of miR­381­mediated regulation of PIK3CA in the development and progression of ovarian cancer and suggest that restoration of miR­381 to normal levels in ovarian cancer cells may constitute a therapeutic strategy for patients.


Assuntos
Adenocarcinoma de Células Claras/genética , Carcinoma Endometrioide/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Endometriose/patologia , MicroRNAs/metabolismo , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Carcinoma Endometrioide/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Progressão da Doença , Endometriose/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Adulto Jovem
18.
Sci Rep ; 7(1): 186, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28298639

RESUMO

Phthalate, an environmental toxin, has been considered as an endocrine-disrupting chemical. Growing evidence has demonstrated links between endocrine-disrupting chemicals, tissue development, and reproductive physiology, but the mechanisms of gene expression regulation by environmental factors that affect cell differentiation are unclear. Herein, we investigated the effects of butyl benzyl phthalate (BBP) on human endometrial mesenchymal stem/stromal cell (EN-MSC) differentiation and identified a novel signaling pathway. Differentiation of endometrial mesenchymal stem/stromal cells decreased after administration of BBP. We analyzed BBP regulation of gene expression in EN-MSC using cDNA microarrays and Ingenuity Pathway Analysis software to identify affected target genes and their biological functions. PITX2 emerged as a common gene hit from separate screens targeting skeletal and muscular disorders, cell morphology, and tissue development. BBP decreased transcription of PITX2 and elevated expression of the microRNA miR-137, the predicted upstream negative regulator of PITX2. These data indicated that BBP affects PITX2 expression through miR-137 targeting of the 3' untranslated region of PITX2 mRNA. PITX2 down-regulation also decreased MyoD transcript levels in EN-MSC. Our results demonstrate that BBP decreases EN-MSC myogenic differentiation through up-regulation of miR-137, contribute to our understanding of EN-MSC differentiation, and underline the hazardous potential of environmental hormones.


Assuntos
Endométrio/citologia , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Desenvolvimento Muscular/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Fatores de Transcrição/genética , Regiões 3' não Traduzidas , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Proteína MyoD/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Homeobox PITX2
19.
Int J Cancer ; 140(8): 1860-1869, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28032649

RESUMO

Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-rasG12D p53loxP/loxP and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated. Induction was widely metastatic and spread to abdominal organs including liver, spleen, and kidney at 4 wk. We also confirmed the role of K-rasG12D in ovarian cancer cell lines MCAS and PA-1 and showed that K-rasG12D overexpression strongly induced cell proliferation, migration, and invasion. The ovarian cancer model we developed recapitulates the specific tumor histomorphology and the probable mechanism of malignant transformation in endometriosis.


Assuntos
Carcinossarcoma/genética , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Animais , Carcinossarcoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Neoplasias Ovarianas/patologia
20.
J Mol Med (Berl) ; 94(7): 835-47, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26920370

RESUMO

UNLABELLED: Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clear cell subtypes. Accordingly, this study had two cardinal aims: first, to obtain mutation profiles of EAOC from Taiwanese patients; and second, to determine whether somatic mutations present in EAOC can be detected in preneoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from ten endometriosis patients with malignant transformation. Macrodissection was performed to separate four different types of cells from FFPE sections in six patients. The four types of samples included normal endometrium, ectopic endometriotic lesion, atypical endometriosis, and carcinoma. Ultra-deep (>1000×) targeted sequencing was performed on 409 cancer-related genes to identify pathogenic mutations associated with EAOC. The most frequently mutated genes were PIK3CA (6/10) and ARID1A (5/10). Other recurrently mutated genes included ETS1, MLH1, PRKDC (3/10 each), and AMER1, ARID2, BCL11A, CREBBP, ERBB2, EXT1, FANCD2, MSH6, NF1, NOTCH1, NUMA1, PDE4DIP, PPP2R1A, RNF213, and SYNE1 (2/10 each). Importantly, in five of the six patients, identical somatic mutations were detected in atypical endometriosis and tumor lesions. In two patients, genetic alterations were also detected in ectopic endometriotic lesions, indicating the presence of genetic alterations in preneoplastic lesion. Genetic analysis in preneoplastic lesions may help to identify high-risk patients at early stage of malignant transformation and also shed new light on fundamental aspects of the molecular pathogenesis of EAOC. KEY MESSAGES: Molecular characterization of endometriosis-associated ovarian cancer genes by targeted NGS. Candidate genes predictive of malignant transformation were identified. Chromatin remodeling, PI3K-AKT-mTOR, Notch signaling, and Wnt/ß-catenin pathway may promote cell malignant transformation.


Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Carcinoma Endometrioide/diagnóstico , Classe I de Fosfatidilinositol 3-Quinases/genética , Endometriose/diagnóstico , Proteínas Nucleares/genética , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/genética , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Endometriose/genética , Endometriose/patologia , Feminino , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inclusão em Parafina , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Fixação de Tecidos , Fatores de Transcrição/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
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